Sensory neurons responsive to painful stimuli, called nociceptors, are crucial for the health of an organism as they are responsible for initiating behavioral responses that prevent or limit tissue damage. Under normal circumstances pain is an important sensation. However, following injury or disease, pain can become persistent, seriously disrupting the lives of those affected. Development and maintenance of nociceptors is known to be dependent on two growth factors, nerve growth factor (NGF) and glial-line derived neurotrophic factor (GDNF). Furthermore, it has been proposed that NGF and GDNF support two different populations of nociceptors and that these two populations are responsible for different types of persistent pain. In addition, changes in nociceptor function induced by NGF and GDNF also modulate nociceptive processing in the adult spinal cord, suggesting a multi-level, growth factor-driven plasticity in the somatosensory system. In our previous studies we determined that NGF plays a dramatic role in determining the "comprehensive phenotype" of nociceptors, influencing physiological, anatomical and functional properties of NGF-dependent nociceptors. The next step is to determine how GDNF affects nociceptors, how changes in NGF and GDNF affect spinal cord neurons receiving nociceptive input, and what affects these changes have on persistent pain. This proposal consists of three Specific Aims employing a "genes to behavior" approach. Specific Aim 1 examines how increases in the level of GDNF affects the comprehensive phenotype of nociceptors. This data will be compared with the results from the NGF studies to provide a complete analysis of the role of growth factors in nociceptor development. Specific Aim 2 examines how NGF- and GDNF- induced changes in nociceptors affects dorsal horn anatomy and neurochemistry. Analysis of spinal cord is crucial because alteration in spinal cord homeostasis can exacerbate or compensate for persistent pain. Specific Aim 3 examines how mice with hypertrophied NGF and GDNF phenotypes respond in two models of persistent pain. Whole animal behavior, nociceptor physiology and changes in dorsal horn neurochemistry will be examined. Upon completion of these specific aims, we anticipate that the differences between NGF- dependent and GDNF-dependent nociceptors will be understood with respect to their anatomical, physiological and neurochemical traits. In addition, it should be possible to identify how these two classes of nociceptors affect dorsal horn development and function. Finally, we will gain insight into how these two classes of nociceptors and their spinal cord targets, respond to induction of persistent pain.